Proteomics reveal cochlin deposits associated with glaucomatous trabecular meshwork
Proteomics reveal cochlin deposits associated with glaucomatous trabecular meshwork
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DOI：
10.1074/jbc.m411233200
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发表时间：
2005-02-18
影响因子：
4.8
通讯作者：
Crabb, JW
中科院分区：
文献类型：
--
作者：
Bhattacharya, SK;Rockwood, EJ;Crabb, JW
原发性开角型青光眼是年龄相关性失明的主要原因之一，其病因学仍不明确，尽管眼内压（IOP）升高有助于疾病进展。为了更好地理解房水循环引起IOP升高的机制，我们对青光眼和年龄匹配的对照供体的小梁网（TM）进行了蛋白质组学分析。这些分析表明，Cochlin，一种与耳聋疾病DFNA 9相关的蛋白质，存在于昏迷性TM中，但在正常TM中不存在。Cochlin也在IOP升高前的青光眼DBA/2 J小鼠的TM中检测到，但在其他三种未发生IOP升高的小鼠系中发现不存在。组织化学分析显示Cochlin和粘多糖在施累姆氏管周围的人TM中的共沉积物，类似于在DFNA 9耳聋的耳蜗中观察到的。发现纯化的Cochlin在剪切应力后聚集并诱导TM细胞在体外聚集。在昏迷TM中观察到Cochlin的E2依赖性体内增加，伴随II型胶原蛋白的减少，表明Cochlin可能破坏TM结构并使胶原蛋白等组分更容易降解和塌陷。总体而言，这些观察结果表明，Cochlin通过改变TM细胞外基质内的相互作用，导致细胞聚集、粘多糖沉积和房水循环的显著阻塞，从而导致原发性开角型青光眼的IOP升高。
The etiology of primary open angle glaucoma, a leading cause of age-related blindness, remains poorly defined, although elevated intraocular pressure (IOP) contributes to the disease progression. To better understand the mechanisms causing elevated IOP from aqueous humor circulation, we pursued proteomic analyses of trabecular meshwork (TM) from glaucoma and age-matched control donors. These analyses demonstrated that Cochlin, a protein associated with deafness disorder DFNA9, is present in glaucomatous but absent in normal TM. Cochlin was also detected in TM from the glaucomatous DBA/2J mouse preceding elevated IOP but found to be absent in three other mouse lines that do not develop elevated IOP. Histochemical analyses revealed co-deposits of Cochlin and mucopolysaccharide in human TM around Schlemm's canal, similar to that observed in the cochlea in DFNA9 deafness. Purified Cochlin was found to aggregate after sheer stress and to induce the aggregation of TM cells in vitro. Age-dependent in vivo increases in Cochlin were observed in glaucomatous TM, concomitant with a decrease in type II collagen, suggesting that Cochlin may disrupt the TM architecture and render components like collagen more susceptible to degradation and collapse. Overall, these observations suggest that Cochlin contributes to elevated IOP in primary open angle glaucoma through altered interactions within the TM extracellular matrix, resulting in cell aggregation, mucopolysaccharide deposition, and significant obstruction of the aqueous humor circulation.